CN112020350A

CN112020350A - Liquid oral pharmaceutical dosage form

Info

Publication number: CN112020350A
Application number: CN201980025867.3A
Authority: CN
Inventors: S·M·穆罕默德; K·林德尔; J·尼尔加德; S·诺德
Original assignee: Johnson and Johnson Consumer Companies LLC
Current assignee: Jinnange Ii Co ltd; Jinnango Zero Co ltd; Johnson and Johnson Consumer Inc
Priority date: 2018-04-27
Filing date: 2019-04-24
Publication date: 2020-12-01
Also published as: US11433024B2; AU2019259791A1; EP3784214A2; AU2019259791B2; US20210106524A1; CA3095103A1; US20220362150A1; WO2019207506A2; EP3784214A4; WO2019207506A3

Abstract

The present disclosure relates to a liquid oral pharmaceutical dosage form comprising a pharmacologically effective amount of at least one histamine H2 receptor antagonist in a hydrophobic/lipophilic liquid that is substantially free of water, comprising at least one viscosity increasing agent, and a pharmacologically effective amount of one or more antacid in a liquid comprising at least one viscosity increasing agent and at least one flavoring agent, wherein the two liquids are physically separated from each other, and wherein the two liquids have matching rheological properties, and a package comprising a plurality of liquid oral pharmaceutical dosage forms and a method of treating a gastric disorder or condition by using said liquid oral pharmaceutical dosage form.

Description

Liquid oral pharmaceutical dosage form

Technical Field

Background

Histamine H2 receptor antagonists, such as cimetidine, ranitidine, nizatidine, roxatidine and famotidine, reduce acid secretion by acting directly on acid-secreting parietal cells within the gastric glands of the gastric wall.

Although histamine H2 receptor antagonists are significantly effective in treating many gastric disorders, particularly peptic and gastric ulcers, there are certain patient populations that do not respond to treatment. Furthermore, the time lapse between administration and onset limits the potential beneficial effects of histamine H2 receptor antagonists in the treatment of acute, self-limiting gastric disorders.

Histamine H2 receptor antagonists have potential beneficial effects in the self-medication of acute, self-limiting gastric disorders such as hyperacidity. However, their slow onset of action may not meet the consumer's need for rapid relief of symptoms.

Co-administration of histamine H2 receptor antagonists and other pharmaceutically active substances, including antacids, has been explored. The basic principle of co-administration with antacids is that antacids rapidly relieve symptoms of gastric hyperacidity by neutralization, whereas histamine H2 receptor antagonists act independently by inhibiting acid secretion from parietal cells.

Antacids in use today are made from a variety of inorganic salts, such as calcium carbonate, sodium bicarbonate, magnesium salts, and aluminum salts. Magnesium hydroxide and aluminum hydroxide are the most effective magnesium and aluminum salts, and are generally used in combination. In addition, magnesium oxide, magnesium carbonate, aluminum phosphate, magnesium aluminate hydrate, magnesium trisilicate, and aluminum sucralfate (sucralfate) may also be used.

To date, it has not been possible to co-administer histamine H2 receptor antagonists such as famotidine with antacids in liquid form. It is well known that the histamine H2 receptor antagonist, famotidine, is very unstable and therefore difficult to prepare stable liquid formulations. Famotidine begins to degrade upon contact with water or any hydrolysis agents and antacids. To date, there has been no product on the market containing famotidine in liquid form due to stability problems. There are reports of stability problems when famotidine is dissolved in a liquid. The antacid may be provided in liquid form dissolved in a water-based liquid without any stability problems.

Many attempts have been made without success to address the medical problems of heartburn and formulation problems (including stability, bitterness) described above, including the disclosures in WO9321932, EP1992345, EP0664701, WO9602262, WO9204893 and WO 2016196205.

Disclosure of Invention

The present invention relates to a liquid oral pharmaceutical dosage form comprising two liquids with different Active Pharmaceutical Ingredients (API) physically separated from each other, wherein one of the liquids is an aqueous liquid and the other is a hydrophobic/lipophilic liquid, i.e. a two-compartment dosage form. However, one problem with such dosage forms is the stability of the liquid, including both chemical stability as well as physical stability. The components need to be chemically compatible and chemically stable with each other. The suspension should be physically stable to reduce settling during shelf life, or readily allow redispersion when simply mixed/shaken prior to application.

Furthermore, the two liquids need to have matching rheological characteristics with respect to each other to be able to fill the packaging in the production plant and to allow simple and equivalent emptying and dose uniformity at the time of use.

Excipients have themselves been selected to be free of off-flavours, and they may further contribute to the taste masking of the Active Pharmaceutical Ingredient (API) or at least not increase the negative perception of API off-flavours.

The excipients must be acceptable for oral administration of the drug, i.e., non-toxic, non-irritating, etc., and should be administered within acceptable daily intakes.

In a first aspect, the present invention relates to a liquid oral pharmaceutical dosage form comprising a) a pharmacologically effective amount of at least one histamine H2 receptor antagonist in a hydrophobic/lipophilic liquid that is substantially free of water and comprises at least one viscosity increasing agent, and b) a pharmacologically effective amount of one or more liquid antacid agents comprising at least one viscosity increasing agent, wherein a) and b) are physically separated.

A ready-to-use dosage form that is consumer friendly, does not require storage in a refrigerator, and is also suitable for use by outworkers. A small discrete dosage form that is easily ingested and prevents degradation of a histamine H2 receptor antagonist, such as famotidine. a) And b) the rheological properties of the liquid should be the same to ensure that the histamine H2 receptor antagonist and the antacid(s) have the same performance and provide the same experience to the consumer at the time of use.

In a second aspect, the present invention relates to a two-compartment stick pack and a two-compartment pouch comprising a liquid oral pharmaceutical dosage form.

In a final aspect, the present invention relates to a method of treating a gastric disorder or condition by using a liquid oral pharmaceutical dosage form comprising a pharmacologically effective amount of at least one histamine H2 receptor antagonist and a pharmacologically effective amount of one or more antacids, as disclosed in the present application.

Detailed Description

Definition of

In the context of the present patent application and invention, the following definitions apply:

the terms "physical barrier" and "physically separated" are intended to mean that the histamine H2 receptor antagonist is separated from the antacid such that they do not come into contact at all during the storage period. The physical barrier prevents the histamine H2 receptor antagonist from coming into contact with any components that may alter and/or degrade the histamine H2 receptor antagonist during the storage period.

The term "substantially free of or free of water" is intended to mean that the water present in the composition is present in an amount of less than about 2% by weight, based on the total weight% of the composition, such as less than 1.5, 1, 0.5, 0.4, 0.3, 0.2, or less than 0.1 or completely free of water, i.e., 0% by weight based on the total weight% of the composition.

The term "% w/w" is intended to mean "percentage of ingredients/total percentage by weight of the composition (100%)".

The term "histamine H2 receptor antagonist" is intended to mean an agent that inhibits the action of histamine and thus reduces the amount of acid produced by gastric secretion, and which is pharmacologically acceptable.

The term "antacid" is intended to mean an agent that acts by neutralizing gastric acid and is pharmacologically acceptable.

The term "viscosifier" is intended to include viscosity modifiers.

The term "matched rheology" is intended to mean that the two liquids have matching rheology to allow an efficient filling process during manufacture of the product and that the two liquids are comfortably administered simultaneously when the two compartments are opened, and that the compartments should be emptied sufficiently to allow the correct dose to be administered.

The term "Medium Chain Triglycerides (MCT)" is intended to mean triglycerides whose fatty acids have an aliphatic tail of 6-12 carbon atoms. The fatty acids present in MCTs are known as Medium Chain Fatty Acids (MCFAs). Like all triglycerides, MCT consists of a glycerol backbone and three fatty acids. For MCT, 2 or 3 of the fatty acid chains attached to glycerol are medium chains in length. Examples include caproic acid (C6:0, common name caproic acid), caprylic acid (C8:0, common name caprylic acid), and capric acid (C10:0, common name capric acid), and dodecanoic acid (C12:0, common name lauric acid).

The term "pharmaceutically effective amount" includes an effective amount to achieve the desired result at the desired dosage and for the desired period of time. The effective amount of the compound may vary depending on various factors, such as the intended dosimetry, the disorder or disease state, the age and weight of the subject.

The term "gastric disorder or disorder" is primarily intended to mean the production of increased acid secretion which leads to heartburn and some annoying bloating symptoms, also known as dyspepsia, in a subject. Dyspepsia, also known as gastric weakness, is a condition in which digestion is impaired. Symptoms may include upper abdominal fullness, heartburn, nausea, abdominal pain, or upper abdominal pain. A person may also experience satiety earlier than expected when eating. Gastric weakness is a common problem and is often caused by gastroesophageal reflux disease (GERD) or gastritis.

Liquid oral pharmaceutical dosage form

The present invention relates to a liquid oral pharmaceutical dosage form comprising a pharmacologically effective amount of at least one histamine H2 receptor antagonist and a pharmacologically effective amount of one or more antacid agents, wherein a physical barrier exists between the histamine H2 receptor antagonist and the antacid agent. The liquid dosage form is a first liquid dosage form in which the histamine H2 receptor antagonist is stable over time.

The at least one histamine H2 receptor antagonist and the one or more antacids are physically separated from each other, i.e. not contacted, before the subject consumes the liquid oral pharmaceutical dosage form, to prevent degradation of the histamine H2 receptor antagonist.

The histamine H2 receptor antagonist is in a hydrophobic/lipophilic liquid substantially free of water and at least one viscosity increasing agent. The hydrophobic/lipophilic liquid may be an oil or a mixture thereof. Examples include medium chain triglycerides, olive oil, coconut oil, linseed oil, palm kernel oil, ethyl oleate or synthetic oils. The oil may also be a super refined oil, such as castor oil, corn oil, cottonseed oil, peanut oil, safflower oil, sesame oil, medium chain triglycerides or soybean oil. By ultra-refined oil is meant, for example, the removal from the oil of polar impurities present in triglycerides, which typically contain monoglycerides, diglycerides, free fatty acids, phytosterols, coloring matter (chlorophyll, carotenes) and oxidation products, as well as other polar substances such as environmental chemicals, thereby providing the oil with some new properties. The super refined oil may be obtained from Croda International Inc. (http:// www.crodahealthcare.com).

Suitable viscosity increasing agents for use in the hydrophobic/lipophilic liquid are selected from ethyl cellulose, lauroyl polyoxylglycerides (such as lauroyl polyoxy-32-glyceride), glyceryl dibehenate, glyceryl distearate, cellulose ethyl ether, fumed silica, e and soybean oil, polyglyceryl-3-dioleate or mixtures thereof. Preference is given to glycerol dibehenate or cellulose ethyl ether or mixtures thereof. Glyceryl dibehenate may be present in an amount of about 1% w/w to about 10% w/w, such as about 2% w/w to about 6% w/w, such as 2.5% w/w, 3.0% w/w, 3.5% w/w, 4.0% w/w, 4.5% w/w, 5.0% w/w, 5.5% w/w, and cellulose ethyl ether is present in an amount of about 0.5% w/w to about 6% w/w, such as about 0.8% w/w to about 2.5% w/w, such as 1.0% w/w, 1.2% w/w, 1.4% w/w, 1.6% w/w, 1.8% w/w, 2.0% w/w, 2.2% w/w, 2.4% w/w.

Dimethicone or mixtures thereof may also be used in place of or in addition to the hydrophobic/lipophilic liquid, as well as an antifoaming agent to reduce flatulence, discomfort and pain.

The hydrophobic/lipophilic liquid may also contain one or more excipients or pH adjusters, such as sweeteners, flavors, coolants, preservatives or colorants. Examples of excipients that may be used are mentioned below. One of the objectives is to provide a dosage form that imparts a smooth coating to the throat.

The H2 receptor antagonist is selected from cimetidine, ranitidine, nizatidine, roxatidine and famotidine, their pharmaceutically acceptable salts, isomers and salts of isomers. One example is famotidine (see examples below).

The one or more antacid may be selected from calcium carbonate, sodium bicarbonate, magnesium hydroxide, aluminium hydroxide, magnesium oxide, magnesium carbonate, aluminium phosphate, magnesium aluminate hydrate, magnesium trisilicate, such as selected from calcium carbonate, sodium bicarbonate, magnesium hydroxide and aluminium hydroxide. One example is a combination of calcium carbonate with magnesium hydroxide or aluminum hydroxide with magnesium hydroxide.

The antacid may be in a water-based liquid comprising one or more excipients and/or a pH adjuster.

To achieve matching rheological properties of the two liquids, it is suitable to use one or more viscosity increasing agents such as polysaccharides, cellulose, sodium carboxymethylcellulose and microcrystalline cellulose or mixtures thereof in the water-based liquid. Other examples of agents are vegetable gums such as xanthan gum, alginates, guar gum, carrageenan, gellan gum, gums, locust bean gum, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and cellulose powder or mixtures or synthetic forms thereof.

The amount of xanthan gum is about 0.05 to about 0.5% w/w, such as 0.1, 0.12, 0.2, 0.25, 0.3, 0.38, 0.4% w/w, and sodium carboxymethyl cellulose and microcrystalline cellulose (Avicel CL)

) The amount of (a) is about 0.4 to about 2% w/w, such as 0.5, 0.6, 0.62, 0.63, 0.7, 0.71, 0.8, 0.85, 0.9, 1.0, 1.1, 1.2, 1.25, 1.5, 1.6, 1.7, 1.8, 1.9% w/w.

Alternatively, the antacid may be in a hydrophobic/lipophilic liquid that is substantially free of water. The hydrophobic/lipophilic liquid may be an oil or a mixture thereof. Examples include medium chain triglycerides, olive oil, coconut oil, linseed oil, palm kernel oil, ethyl oleate or synthetic oils. The oil may also be a super refined oil, such as castor oil, corn oil, cottonseed oil, peanut oil, safflower oil, sesame oil, medium chain triglycerides or soybean oil. By ultra-refined oil is meant, for example, the removal from the oil of polar impurities present in triglycerides, which typically contain monoglycerides, diglycerides, free fatty acids, phytosterols, coloring matter (chlorophyll, carotenes) and oxidation products, as well as other polar substances such as environmental chemicals, thereby providing the oil with some new properties. The super refined oil may be obtained from Croda International Inc. (http:// www.crodahealthcare.com). Famotidine can be formulated with other active ingredients such as dimethicone to control flatulence or alginic acid or a salt thereof to act as a physical barrier.

Simethicone, dimethicone or mixtures thereof and other solvents/excipients may also be used in place of or in addition to the hydrophobic/lipophilic liquid, as well as an anti-foaming agent to reduce fullness, discomfort and pain. In hydrophobic/lipophilic liquids, such as those mentioned above in relation to H2 receptor antagonists.

Examples of flavoring agents suitable for use in the histamine H2 receptor antagonist liquid and/or the antacid liquid include peppermint, licorice, herbs, bubble gum, vanilla, caramel, raspberries such as strawberry, blackcurrant, blueberry, and cherry, mint, and lemon.

The liquid compositions of the present invention are suspensions that contain the active ingredient in an admixture with pharmaceutically acceptable excipients typically found in oral suspensions. Such excipients may be suitable suspending agents, for example sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, xanthan gum, locust bean gum and cellulose derivatives, such as sodium carboxymethylcellulose, microcrystalline cellulose, hydroxyethyl cellulose, methyl cellulose or hydroxypropyl methyl cellulose, or mixtures thereof. Dispersing or wetting agents such as sorbitan esters or lecithin, anti-gelling additives, surface modifiers, aqueous or non-aqueous vehicles such as sorbitol solutions, ethanol or fractionated vegetable oils, or diluents may also be included.

Sometimes a preservative component may be used if desired. Such preservative component may be selected from any pharmaceutically acceptable preservative. Alkyl esters of parahydroxybenzoic acid (parabens, such as butyl parahydroxybenzoate, methyl parahydroxybenzoate, and propyl parahydroxybenzoate) are exemplified, and may be used alone or in combination. Generally, parabens are used at a concentration of about 0.02% w/w. Other preservatives include ethylenediamine tetraacetic acid, propyl parabens, antioxidants, or sorbic acid.

The composition may also contain coloring agents and/or sweetening agents as the case may be. The sweetener may be, for example, a bulk sweetener such as sugar (e.g. sucrose or fructose) or a polyol (e.g. maltitol, xylitol, sorbitol, sucralose) and/or an intense sweetener such as saccharin, aspartame, or acesulfame k.

Other active agents may be added to the preparation. For example, alginates, antiflatulents, analgesics, antidiarrheals, antispasmodics or anti-foaming agents such as simethicone, and other gastrointestinal agents may be added in dosages conventionally used to treat gastrointestinal dysfunction (including dyspepsia).

Examples of liquid oral pharmaceutical dosage forms include a two-compartment sachet or stick pack, wherein one of the compartments contains an H2 receptor antagonist, such as famotidine, and the other compartment contains one or more antacids. The compartments may be separated from each other by means of a perforation line and provide an easy-to-open opening on one side.

In one embodiment, a liquid oral pharmaceutical dosage form comprises

a) A pharmacologically effective amount of famotidine in an MCT, which is substantially free of water and further comprises a viscosity increasing agent which is a mixture of glyceryl dibehenate and cellulose ethyl ether.

b) A liquid, pharmacologically effective amount of calcium carbonate and magnesium hydroxide, at least one viscosity increasing agent, and at least one flavoring agent, wherein a) and b) are physically separated from each other, and wherein a) and b) have matching rheological properties.

Dosage of liquid oral pharmaceutical dosage form

A histamine H2 receptor antagonist such as famotidine may be present in an amount from about 2mg to about 30mg, such as 4mg to 20mg or 8mg to 12mg or 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 226mg, 27mg, 18mg, 19mg or 30 mg.

The antacid may be present in an amount of about 200mg to about 3000 mg. If two different antacids are utilized, they may be in the same amount or different amounts, depending on the particular combination. Exemplified are liquid oral pharmaceutical dosage forms having calcium carbonate in an amount of about 400mg to about 1000mg, such as 600mg, 700mg, 800mg, 900mg or 1000mg, and magnesium hydroxide may be present in an amount of about 50mg to about 300mg, such as about 100mg to about 200mg, such as 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 165mg, 170mg, 180mg, 190mg or 200 mg. If alumina is used, it is used in an amount of about 200mg to about 600mg, such as 300mg, 400mg, 416mg, 500mg, or 600 mg.

a) Or the amount of liquid in b) may be from about 2ml to about 20ml, such as from about 2ml to about 10ml, such as 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml or 10ml, respectively. a) The amounts in a) and b) may be the same or different, depending on the formulation of a) and b) and the form of the dosage form.

The invention also relates to a package comprising a plurality of liquid oral pharmaceutical dosage forms as defined above.

Finally, the present invention relates to a method of treating a gastric disorder or disorder by using a liquid oral pharmaceutical dosage form as disclosed above.

In order to further illustrate the present invention and its advantages, the following specific examples are given, it being understood that these examples are intended to be illustrative only and are not limiting upon the scope of the invention.

Examples

Example 1

Material

All oils were obtained from Croda International.

Magnesium hydroxide and calcium carbonate were obtained from Magnesia Gmbh.

Famotidine is available from Gedeon Richter, Hungary, and is film coated internally using conventional coating techniques well known to those skilled in the art.

Preparation

Different kinds of formulations were prepared and are shown in table 1.

Famotidine was mixed in different kinds of solvents, including different oils, to investigate which oils are suitable for use with famotidine (samples 1-11 and 22-25 in table 1). The results show that famotidine is stable in all oils, and is most stable in the presence of medium chain triglycerides (samples 8F1/F2, 22C, 23A/B, 24A and 25B 7).

Different antacid mixtures were studied to determine which might be appropriate (samples 12-21 in Table 1).

Two compartment package

A two-compartment package in which a two-compartment sachet made of laminated aluminium foil is produced. The three layers of aluminum foil were sealed to each other to form a two-compartment package to be filled with different formulations. The sachet is prepared to allow simultaneous opening of both compartments. 5ml of sample 8 (uncoated famotidine) was introduced into one of the compartments and 5ml of sample 12 was introduced into the other compartment. The two-compartment package is sealed.

TABLE 1

Example 2

Analysis of the stability of famotidine suspended in different oils.

Uncoated famotidine was mixed in one of the following oils: safflower oil (B1), soybean oil (B2), sesame oil (B3), corn oil (B4), cotton seed oil (B5), super-refined MCT (B6) and standard MCT (B7). 3 samples were prepared per batch and incubated at 40/75 ℃, 50 ℃ or 60 ℃. Famotidine, 10mg, was mixed with 5g of oil. Samples were taken after 14 days, 1 month, 2 months, and 3 months and famotidine stability was evaluated.

For stability analysis, samples were prepared and analyzed using the following method

Solutions of

Mobile phase

Famotidine standard

Famotidine: CAS number: 76824-35-6, C₈H₁₅N₇O₂S₃，MW：337.45

Sample preparation

Pour the sample from the sample bottle into a 100ml volumetric flask.

Rinse the vial at least 3 times into the volumetric flask with diluent.

Fill the volumetric flask with diluent to about 70 ml.

Shake the sample for 45 minutes.

Fill volumetric flasks with diluent up to 100 ml.

Mix the samples.

The sample was filtered and transferred to an LC vial for LC-UV analysis. (Millex HV Hydrophilic PVDF 0.45 μm)

Parameters of the instrument

Column: ACE, C8, 3 μm, 150mm × 4.6mm

Flow rate: 1.0ml/min

Gradient:

sample introduction volume: 10 μ l

Column temperature: 35 deg.C

And (3) detection: UV 278nm

na denotes no analysis

The results of the stability tests showed that famotidine was stable in all oils and was most stable when mixed with either standard purity MCT oil or refined MCT (samples B6 and B7).

Example 3

The viscosity and consistency of the different antacid formulations were evaluated.

Varying amounts of xanthan gum 180 and Avicel CL 611NF were used.

TABLE 2

TABLE 3 formulation with a viscosity modifier

Table 4 formulation with two viscosity modifiers

TABLE 5 formulation with a viscosity modifier plus dimethicone

Example 4

Rheological analysis was performed on 4 samples to evaluate the performance of the different excipient mixtures.

The results are shown in FIG. 1. With increasing Ethocel Standard 45 premium ratio, an increase in shear thinning behavior was observed. The viscosity of Ethocel polymer is known to be stable to high temperatures.

Claims

1. A liquid oral pharmaceutical dosage form comprising

a) A pharmacologically effective amount of at least one histamine H2 receptor antagonist in a hydrophobic/lipophilic liquid which is a substantially water-free oil comprising at least one viscosity increasing agent, wherein the viscosity increasing agent is selected from the group consisting of ethylcellulose polymer, lauroyl polyoxylglyceride, glyceryl dibehenate, cellulose ethyl ether, glyceryl distearate, fumed silica, or mixtures thereof

And

b) a pharmacologically effective amount of one or more antacid(s) in a liquid comprising at least one viscosity increasing agent selected from the group consisting of vegetable gums such as alginates, guar gum, locust bean gum, xanthan gum, carrageenan, gellan gum or polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and cellulose powder or mixtures thereof, wherein a) and b) are physically separated from each other, and wherein a) and b) have matching rheological properties, and at least one flavor agent.

2. The liquid oral pharmaceutical dosage form according to claim 1, wherein the H2 receptor antagonist is selected from cimetidine, ranitidine, nizatidine, roxatidine and famotidine, their pharmaceutically acceptable salts, isomers and salts of isomers.

3. The liquid oral pharmaceutical dosage form of claim 2, wherein the H2 receptor antagonist is famotidine.

4. The liquid oral pharmaceutical dosage form according to any one of the preceding claims, wherein the viscosity increasing agent in a) is a mixture of glyceryl dibehenate and cellulose ethyl ether.

5. The liquid oral pharmaceutical dosage form according to claim 5, wherein glyceryl dibehenate is present in an amount from about 1% w/w to about 10% w/w, and cellulose ethyl ether is present in an amount from about 0.5% w/w to about 6% w/w.

6. The liquid oral pharmaceutical dosage form according to any one of the preceding claims, wherein the oil is selected from medium chain triglycerides, olive oil, coconut oil, linseed oil, palm kernel oil, ethyl oleate, synthetic oils, castor oil, corn oil, cottonseed oil, peanut oil, safflower oil, sesame oil or soybean oil.

7. The liquid oral pharmaceutical dosage form of claim 10, wherein the oil is super refined.

8. The liquid oral pharmaceutical dosage form of claim 10, wherein the oil is a medium chain triglyceride.

9. The liquid oral pharmaceutical dosage form according to any of the preceding claims, wherein the one or more antacid agents are selected from calcium carbonate, sodium bicarbonate, magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, aluminum phosphate, magnesium aluminate hydrate and magnesium trisilicate.

10. The liquid oral pharmaceutical dosage form according to claim 13, wherein the one or more antacid agents are selected from calcium carbonate, magnesium hydroxide and aluminum hydroxide.

11. The liquid oral pharmaceutical dosage form according to claim 13, wherein the one or more antacid agents is a combination of calcium carbonate and magnesium hydroxide or aluminum hydroxide and magnesium hydroxide.

12. The liquid oral pharmaceutical dosage form according to any preceding claim, wherein the flavoring agent is selected from peppermint, spearmint, eucalyptus, licorice, vanilla, herbaceous plants, caramel, berry or mixed berry, mixed fruit, blackcurrant, blueberry, cherry, lemon, and mixtures thereof.

13. The liquid oral pharmaceutical dosage form according to any of the preceding claims, comprising dimethicone or polydimethylsiloxane or a mixture thereof or alginate in a) and/or b).

14. The liquid oral pharmaceutical dosage form of any of the preceding claims, wherein famotidine is present in an amount from about 2mg to about 30 mg.

15. The liquid oral pharmaceutical dosage form of any of the preceding claims, wherein the antacid is present in an amount of about 200mg to about 3000 mg.

16. The liquid oral pharmaceutical dosage form according to any of the preceding claims, wherein the liquid formulations in a) and b) are present in an amount of from about 2ml to about 20ml, respectively.

17. The liquid oral pharmaceutical dosage form according to any of the preceding claims, which is a two-compartment stick pack or a two-compartment pouch.

18. A method of treating a gastric disorder or disorder by using a liquid oral pharmaceutical dosage form according to any one of claims 1 to 17.